3-11026351-C-A

Variant names:

• chr3-11026351-C-A
• rs1553689859
• NM_003042.4:c.1070C>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_003042.4(SLC6A1):​c.1070C>A​(p.Ala357Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A357V) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC6A1 NM_003042.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.65
• Publications: 1 publications found

Genes affected

SLC6A1 (HGNC:11042): (solute carrier family 6 member 1) The protein encoded by this gene is a gamma-aminobutyric acid (GABA) transporter that localizes to the plasma membrane. The encoded protein removes GABA from the synaptic cleft, restoring it to presynaptic terminals. [provided by RefSeq, Jan 2017]

SLC6A1 Gene-Disease associations (from GenCC):

• epilepsy with myoclonic atonic seizures

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Illumina, G2P, Labcorp Genetics (formerly Invitae)
• myoclonic-astatic epilepsy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_003042.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-11026351-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 542198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 3-11026351-C-A is Pathogenic according to our data. Variant chr3-11026351-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1299344.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A1	NM_003042.4	c.1070C>A	p.Ala357Glu	missense_variant	Exon 10 of 16	ENST00000287766.10	NP_003033.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A1	ENST00000287766.10	c.1070C>A	p.Ala357Glu	missense_variant	Exon 10 of 16	1	NM_003042.4	ENSP00000287766.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461270 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726928

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111738

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epilepsy with myoclonic atonic seizures Pathogenic:1

Oct 01, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;D;D;D;D;.;D;.;D;D;D;D;.;D;D;D;.;D;D;D;.;D;D;D;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;D;.;.;D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.7	H;H;H;H;H;.;H;.;H;H;H;H;.;H;H;H;.;H;H;H;.;H;H;H;.;.
PhyloP100		7.7
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.8	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0010	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;D;D;D;D;.;D;.;D;D;D;D;.;D;D;D;.;D;D;D;.;D;D;D;.;.
Vest4		0.90
MutPred		0.85		Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);.;Gain of disorder (P = 0.0266);.;Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);.;Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);.;Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);.;Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);
MVP		0.95
MPC		2.3
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.97
gMVP		0.97
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553689859; hg19: chr3-11068037;